MicroRNAs as Biomarkers of Germ Cell Tumors-Focus on Impact and Limitations in Current Clinical Practice Paradigms

Testicular germ cell tumors (TGCTs) are the most common malignancies in young-adult males and represent a biologically heterogeneous group of neoplasms. Despite excellent overall prognosis, conventional serum tumor markers lack sufficient sensitivity and specificity in several key clinical settings, including early metastatic disease, postchemotherapy residual masses, and surveillance. Over the past decade, microRNAs of the miR-371~373 cluster have emerged as highly accurate biomarkers in this setting. Among them, circulating miR-371a-3p has demonstrated sensitivity and specificity exceeding 90% for viable, nonteratomatous TGCTs across multiple cohorts, consistently outperforming traditional markers. miR-371a-3p levels closely reflect tumor burden, showing rapid decline after orchiectomy and during effective chemotherapy, and rising at relapse, enabling near real-time disease monitoring. Importantly, miR-371~373 is differentiation-dependent (which can be used as readout for studies on the pathobiology of TGCT phenotypes). It is present in nonteratomatous germ cell components, uniformly absent in teratoma and absent/low in somatic-type malignancies, a feature that both underpins its clinical utility and defines one of its main limitations. This review summarizes the biological rationale underlying miR-371~373 expression in TGCTs and examines current clinical applications of miR-371a-3p across diagnosis, staging, surveillance, and postchemotherapy assessment. Moreover, we discuss analytical considerations, health-economic implications, and emerging data in the biologically related ovarian and extragonadal germ cell tumors. Remaining challenges and future directions for standardized clinical implementation are also addressed.